Stroke is the 3rd leading cause of death in the United States and is the major disabling neurological disease of adults, particularly the elderly. Risk factors predisposing to stroke have been identified through prospective epidemiologic studies including the Framingham Heart Study. Control of stroke risk factors has guided preventive efforts and has led to significant reduction in death and disability from stroke; however, much work remains to be done. Since 1981, the Precursors of Stroke Incidence and Prognosis study has enabled us to identify risk factors for stroke, report on secular trends, lifetime risk and manifestations of stroke and of specific stroke subtypes using consistent clinical and imaging criteria. Twelve hundred nineteen completed strokes have been documented to date. We plan to maintain surveillance and identify incident and recurrent strokes in this 3 generation community- based epidemiologic study and to personally evaluate subjects at the time of stroke in the local hospital, and at 3, 6, 12 and 24 months. We will systematically assess neurological, imaging (MRI & MRAs), functional, cognitive and mood outcomes in these subjects and provide estimates of lifetime risk, secular trends in stroke risk factors, incidence and recurrence, case fatality, disability, and institutionalization. In this renewal we propose to utilize an extensive panel of biomarkers, measured prior to stroke and to relate genoptypic data from a 550K Genome Wide Association study to stroke incidence and outcomes. These exciting and innovative additions are available as a result of funding from other NIH sources to the Framingham Heart Study and hold promise to add new insights to the identification of stroke susceptibility. In addition, a wealth of previously collected subclinical vascular disease measures are available including: echocardiography, carotid ultrasound, MRI and CT scans of the heart and aorta; vascular function studies - arterial stiffness, ankle-brachial index and brachial artery reactivity; and baseline and repeated quantitative brain MR scans, including silent strokes on >2,400 Offspring subjects. These indicators of subclinical cardiac and vascular disease may greatly enhance our ability to identify susceptible stroke-prone individuals. It is anticipated that adding this wide array of biomarker, GWA and subclinical disease data to conventional and newer risk factor measures will facilitate better stroke prediction by an improved Stroke Risk Profile. PUBLIC HEALTH RELEVANCE: The public health burden of stroke is substantial in our aging population. The goal of this renewal application is to continue to prospectively identify health and genetic factors that contribute to placing a person at high risk of stroke. Understanding these interactions will advance our ability to formulate strategies to prevent stroke and minimize disability resulting from stroke.